Development anew delivery systems for gene and drug transport for diseases associated with inflammation including cancer, stroke, traumatic brain injury (TBI), neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases (PD and AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), lysosomal storage diseases, age-related macular degeneration (AMD), Prion disease, meningitis, encephalitis and HIV-1-associated dementia (HAD), mental disorders such as depression, autism, and schizophrenia and others is greatly needed. The challenges faced are: decreased extravasation to the target side such as due to limited blood brain barrier (BBB) permeability, inherent peripheral and brain drug toxicities, and low therapeutic indices. Immunocytes, mononuclear phagocytes (MP; monocytes, macrophages, and dendritic cells), lymphocytes, and neutrophils, as well as stem cells exhibit an intrinsic homing property enabling them to migrate to sites of injury, inflammation, and tumor across the EBB in response to the release of cytokines/chemokines and upregulation of certain cell surface proteins in the diseased tissues and nearby blood vessels. Even in the healthy brain, perivascular macrophages, which reside on the parenchymal side of endothelial cells, originally come from circulating phagocytes, monocytes and macrophages and have shown a remarkable capability to cross an intact BBB with 80% turnover in 3 months. Many reports in the literature indicate that leukocytes traffic primarily between adjacent endothelial cells through the junctional complexes (paracellular migration), or in some cases through the endothelial cell itself (transcellular migration). Under pathological conditions, the rate of immunocytes transport to the inflamed brain tissues is further elevated. The pathobiology of PD, AD and other neurodegenerative diseases is linked to microglial activation and subsequent secretion of neurotoxic factors. These include reactive oxygen and nitrogen species (ROS and RNS) leading to oxidative stress (McGeer et al. (1988) Neurology 38:1285-1291; Busciglio et al. (1995) Nature 378:776-779; Ebadi et al. (1996) Prog. Neurobiol., 48:1-19; Wu et al. (2003) Proc. Natl. Acad. Sci., 100:6145-6150), which affects neuronal, astrocyte, and microglia function by inducing ion transport and calcium mobilization, and activating apoptotic programs. Apoptosis and excitotoxicity are principal causes of mitochondrial-induced neuronal death (Arends et al. (1991) Int. Rev. Exp. Pathol., 32:223-254). Indeed, the mitochondrial respiratory chain affects oxidative phosphorylation and is responsible for ROS production. Such pathways lead to neuronal demise and underlie the pathobiology of PD and AD (Chan, P. H. (2001) J. Cereb. Blood Flow Metab., 21:2-14).
The lack of natural antioxidants (catalase, glutathione and superoxide dismutase) and iron in the substantia nigra (SN) are specifically associated with the pathobiology of PD (Ambani et al. (1975) Arch. Neurol., 32:114-118; Riederer et al. (1989) J. Neurochem., 52:515-520; Abraham et al. (2005) Indian J. Med. Res., 121:111-115). Removing ROS and affecting mitochondria function through targeted delivery of redox enzymes could attenuate disease progression (Gonzalez-Polo et al. (2004) Cell Biol. Int., 28:373-380). Therefore, efficient brain delivery of redox enzymes, such as catalase and superoxide dismutase, or their replicative genetic material can attenuate ROS and improve disease outcomes. Unfortunately, antioxidants when administered as therapeutic agents fail to alter the course of PD-associated neurodegeneration (Pappert et al. (1996) Neurology 47:1037-1042). Such failures may be a result from limited delivery of antioxidants at disease sites. Accordingly, better methods for the delivery of therapeutics such as antioxidants are needed.